JAK2/STAT5/Bcl-xL signalling is essential for erythropoietin-mediated protection against apoptosis induced in PC12 cells by the amyloid β-peptide Aβ25-35.
BRITISH JOURNAL OF PHARMACOLOGY(2014)
摘要
Background and Purpose Erythropoietin (EPO) exerts neuroprotective actions in the CNS, including protection against apoptosis induced by the amyloid -peptide A25-35. However, it remains unclear which signalling pathway activated by EPO is involved in this neuroprotection. Here, we have investigated whether JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways are essential for EPO-mediated protection against apoptosis induced by A25-35. Experimental Approach EPO was added to cultures of PC12 cells, 1h before A25-35. For kinase inhibitor studies, AG490 and PD98059 were added to PC12 cells, 0.5h before the addition of EPO. Transfection with siRNA was used to knockdown STAT5. Activation of JAK2/STAT5/Bcl-xL and ERK1/2 signalling pathways were investigated by Western blotting. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide assay and apoptosis was detected by TUNEL and acridine orange-ethidium bromide double staining. Key Results EPO increased phosphorylation of JAK2 and STAT5 in PC12 cells treated with A25-35. Furthermore, EPO modulated the nuclear translocation of phospho-STAT5, which increased expression of Bcl-xL and decreased levels of caspase-3. These beneficial effects were blocked by the JAK2 inhibitor, AG490 or STAT5 knockdown. However, the ERK1/2 pathway did not play a crucial role in our model. Conclusions and Implications EPO protected PC12 cells against A25-35-induced neurotoxicity. Activation of JAK2/STAT5/Bcl-xL pathway was important in EPO-mediated neuroprotection. EPO may serve as a novel protective agent against A25-35-induced cytotoxicity in, for instance, Alzheimer's disease.
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关键词
erythropoietin,A,apoptosis,kinase inhibitor,JAK2,STAT5,ERK1,2
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